The production and distribution of influenza vaccines as well as delivery by medical personnel is extremely time consuming, as seen during the prolonged and inefficient annual vaccination campaigns. To expedite vaccination, this project proposes to develop microneedle-based influenza vaccine patches that can be self-administered;do not produce sharp, biohazardous waste;and are low cost. Such patches could be rapidly distributed through pharmacies, fire stations or even the U.S. mail. Because microneedle patches target delivery to the skin's dendritic cells, lower vaccine doses should be needed, which is vital when vaccine supplies are limited. To accomplish these goals, this project has three Specific Aims. Aim 1 will develop novel microneedle systems that are designed to deliver influenza vaccines to the skin. Microfabrication techniques will be developed to make microneedles that easily insert into skin to rapidly deliver vaccine to targeted depths. Microneedle designs will be compared in terms of their mechanical properties;stability during processing and storage;controlled dose targeting and kinetics of vaccine delivery. Aim 2 will evaluate the efficacy of influenza vaccines delivered using microneedles to mice and hairless guinea pigs. Inactivated virus, detergent-split virus and purified HA protein will be compared as alternative vaccines, and selected adjuvants will be evaluated for their ability to enhance immune responses. The microneedle design and vaccination protocol will be optimized based on measuring humoral immune responses and protection against virus challenge. Secondary criteria will include cellular immune responses and memory B cell repertoire. Aim 3 will determine the safety and stability of selected vaccine formulations, followed by GMP manufacturing of a pilot lot of the final product, and safety and toxicology studies of the final product. While the focus of the present application is on developing this system for prevention of seasonal influenza, the resulting information should also be applicable to novel vaccines for prevention of pandemic influenza.